This proposal focuses on the development of peptide-based antiviral agents that can selectively block assembly of enveloped viruses. The structures of the peptides correspond to short sequences of amino acids in the cytoplasmic domains of viral transmembranal glycoproteins that are postulated to interact with viral matrix proteins and nucleocapsids during virus assembly. Preliminary results showing that the addition of such peptides to cultured cells infected with influenza, vesicular stomatitis or Sindbis viruses inhibit release of newly synthesized viruses indicate that this approach has therapeutic potential. Inhibition was selective for the peptide specific to the individual virus and did not affect host cells under the conditions tested. We plan to extend our preliminary results with influenza virus by determining the structure of the smallest peptide that is most effective for inhibiting release of infectious virions. From these data, non- peptide compounds whose structures are based on conformational mimicry would be synthesized and tested for therapeutic potency in a variety of biological systems. In addition peptides mimicking cytoplasmic domains of glycoproteins in respiratory syncytial virus and the vaccine strain of yellow fever virus (used as a model system for human pathogenic flaviviruses) will be tested with laboratory-adapted strains growing in cultured cells.